Mechanisms of resistance in small cell lung cancer

ABSTRACT: Small cell lung cancer (SCLC) is the most aggressive histological subtype of lung cancer and is characterized by rapid tumor proliferation, early dissemination, and poor prognosis. Currently, the standard first-line treatment for extensive-stage SCLC consists of platinum-based chemotherapy and immune checkpoint inhibitors. Although patients exhibit a high initial response rate to platinum-based chemotherapy, the majority develop acquired resistance within 6 months. Overcoming drug resistance and prolonging the duration of first-line therapy are critical for long-term survival in these patients. However, the definitive resistance mechanisms associated with chemotherapy and immunotherapy in SCLC remain unclear. In this context, we comprehensively review the diverse mechanisms contributing to therapeutic resistance in SCLC, including transcriptional subtype plasticity, the epithelial-mesenchymal transition, an enhanced DNA damage repair capacity, dysregulated autophagy and apoptosis, the presence of cancer stem cells, alterations in the tumor microenvironment, and the aberrant expression of cellular transporters. We particularly focus on the dynamic evolution of resistance from intrinsic to acquired states and the complex interplay among these mechanisms, aiming to provide an integrated theoretical framework to guide the development of rational combination strategies to overcome therapeutic resistance.